title: A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment.
abstract: In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation εL221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human ε-subunits harbouring an EGFP tag within the M3-M4 cytoplasmic region, driven by a ~1500 bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89 ± 3 ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these β2-adrenergic receptor agonists for the treatment of the slow channel syndrome.
authors.affiliation: Neurosciences Group, Nuffield Dept. of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: R G
authors.initials: RG
authors.lastname: Webster
authors.forename: J
authors.initials: J
authors.lastname: Cossins
authors.forename: D
authors.initials: D
authors.lastname: Lashley
authors.forename: S
authors.initials: S
authors.lastname: Maxwell
authors.forename: W W
authors.initials: WW
authors.lastname: Liu
authors.forename: J R
authors.initials: JR
authors.lastname: Wickens
authors.forename: P
authors.initials: P
authors.lastname: Martinez-Martinez
authors.forename: M
authors.initials: M
authors.lastname: de Baets
authors.forename: D
authors.initials: D
authors.lastname: Beeson
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004809:Ephedrine / Q000494:pharmacology / Q000627:therapeutic use*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics / Q000503:physiopathology*; D011950:Receptors, Cholinergic / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D018663:Adrenergic Agents; D011950:Receptors, Cholinergic; D004809:Ephedrine
keywords: Acetylcholine receptor; Congenital myasthenia; Electromyography; Ephedrine; Fluorescent endplates; Mouse model; Neuromuscular junction; Slow channel syndrome